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Prospects for extending healthy life - a lot Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton PowerPoint Presentation
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Prospects for extending healthy life - a lot Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton, VA, USA and Cambridge, UK Email: aubrey@sens.org MF site: http://www.methuselahfoundation.org/ Science site: http://www.sens.org/ Prize site: http://www.mprize.org/.

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slide1

Prospects for extending healthy life - a lot

Aubrey D.N.J. de Grey, Ph.D.

Chairman and CSO, Methuselah Foundation

Lorton, VA, USA and Cambridge, UK

Email: aubrey@sens.org

MF site: http://www.methuselahfoundation.org/

Science site: http://www.sens.org/

Prize site: http://www.mprize.org/

slide2

Shameless plug

Out now: $17.79 at Amazon

slide4

Fun Not fun

Why I am doing this

slide5

Structure of this talk

  • Repair versus retardation
  • Longevity escape velocity: concept
  • Some evidence that LEV is realistic
  • Specifics: the seven types of damage
  • Intracellular junk/medical bioremediation
  • The Methuselah Foundation
slide6

Structure of this talk

  • Repair versus retardation
  • Longevity escape velocity: concept
  • Some evidence that LEV is realistic
  • Specifics: the seven types of damage
  • Intracellular junk/medical bioremediation
  • The Methuselah Foundation
slide7

Aging in a nutshell

Product of evolutionary nelect, not intent

Metabolism ongoingly causes “damage”

Damage eventually causes pathology

Pathology causes more pathology

slide8

Strategies for intervention

Gerontology Geriatrics

Metabolism Damage Pathology

slide11

Strategies for intervention

Gerontology Engineering Geriatrics

Metabolism Damage Pathology

Claim: unlike the others, the engineering approach may achieve a large extension of human healthy lifespan quite soon

slide12

Structure of this talk

  • Repair versus retardation
  • Longevity escape velocity: concept
  • Some evidence that LEV is realistic
  • Specifics: the seven types of damage
  • Intracellular junk/medical bioremediation
  • The Methuselah Foundation
slide13

Reasons for the engineering approach

  • it targets initially inert intermediates (“damage”)
slide14

Reasons for the engineering approach

  • it targets initially inert intermediates (“damage”)
  • repairing damage buys time
slide15

Retarding aging: benefits modest

max

Reserve

frail

0

0

Age

Halving rate of damage starting in middle age

- doubles remaining healthspan

- raises total healthspan by maybe 20%

slide16

Comparable repair: far better

max

hard

Reserve

easy

frail

0

0

Age

Fixing half the damage starting in middle age

- doubles total healthspan

- raises remaining healthspan maybe 5-fold

slide17

Robust human rejuvenation (RHR)

Addition of 30 extra years of healthy life (and total life) to people who are already in middle age when treatment is begun

slide18

Ever-improving repair: better yet

max

very hard

Reserve

hard

easy

frail

0

0

Age

Fixing half the damage, then 3/4

- not as good as doing 3/4 first time…

- but better than doing 1/2 first time…

slide19

Infinitely better, in fact

max

Reserve

frail

0

0

Age

Fixing half the damage, then 3/4, then 7/8….

- outpaces the so-far-unfixable damage…

- maintains healthspan indefinitely

slide20

Longevity escape velocity (LEV)

The rate at which rejuvenation therapies must improve (following the achievement of RHR) in order to outpace the accumulation of so-far-irreparable damage

slide21

Structure of this talk

  • Repair versus retardation
  • Longevity escape velocity: concept
  • Some evidence that LEV is realistic
  • Specifics: the seven types of damage
  • Intracellular junk/medical bioremediation
  • The Methuselah Foundation
slide22

Simulating aging

(Phoenix & de Grey, AGE, in press)

Metabolism ongoingly causes “damage”

and

Damage eventually causes pathology

So….

Simulations of aging (and intervention) should simulate damage accumulation

slide23

Simulating damage: basis

  • damage of many types accumulates
  • any can kill us (i.e. they are not additive)
  • within each type, subtypes are additive
  • damage feeds back to hasten more damage
  • people differ in damage accumulation rates
  • death is from damage X challenge (e.g. flu)
slide24

Simulating damage: model

Structural parameters

N_CAT: The number of damage categories each person has N_MECH: The number of mechanisms in each category

MECH_WEIGHTm: The contribution of a mechanism to a category

Fitting parameters

BASAL_M: The mean basal damage rate BASAL_SD: The standard deviation of the basal damage rate

BASAL_H: The homogeneity of basal damage rate in a single person EXP_M: The mean exponential damage rate

EXP_SD: The standard deviation of the exponential damage rate

EXP_H: The homogeneity of exponential damage rate in a single person

FATAL_M: The mean yearly challenge FATAL_SD: The standard deviation of the yearly challenge

Values set for each person at initialisation:

PB: Basal rate for the person: lognorm(BASAL_M, BASAL_SD)

PE: Exponential rate for the person: lognorm(EXP_M, EXP_SD)

MBc,m:Basal rate for each mechanism: lognorm(BASAL_M, BASAL_SD)*(1-BASAL_H) + PB*BASAL_H

MEc,m: Exponential rate for each mechanism: lognorm(EXP_M, EXP_SD)*(1-EXP_H) + PE*EXP_H

D_Mc,m : Cumulative damage for each mechanism: 0 D_Cc : Cumulative damage for each category: 0

Variables updated for each person at each time step (year):

Total damage: PD(t) = [SUM c=1..N_CAT] D_Cc(t) Damage increment: DI_Mc,m(t) = MBc,m + MEc,m*PD(t-1)

Cumulative damage: D_Mc,m(t) = DI_Mc,m(t) + D_Mc,m(t-1)

Cumulative category damage: D_Cc(t) = [SUM m=1..N_MECH] DI_Mc,m(t)

Fatality challenge: FATAL(t) = |norm(FATAL_M, FATAL_SD)|

If D_Cc(t) > FATAL(t) for any c, the person dies at age t

slide27

Results: defeat of damage

Therapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350

slide28

Results: LEV in practice

Therapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350

slide29

LEV decreases with time

max

Reserve

frail

0

0

Age

Fixing half the damage, then 2/3, then 3/4….

- still good enough…

- just like gravitational escape velocity

slide31

Structure of this talk

  • Repair versus retardation
  • Longevity escape velocity: concept
  • Some evidence that LEV is realistic
  • Specifics: the seven types of damage
  • Intracellular junk/medical bioremediation
  • The Methuselah Foundation
slide32

Reasons for the engineering approach

  • it targets initially inert intermediates (“damage”)
  • repairing damage buys time
  • damage is simpler than metabolism or pathology
slide34

Problem 2:this is the pathology

  • Cancer
  • Heart Disease
  • Diabetes
  • Incontinence
  • Osteoporosis
  • Macular Degeneration
  • Alzheimer’s
  • Stroke
  • Sarcopenia
  • Osteoarthritis
  • Hormonal Imbalance
  • Kidney Failure
  • Parkinson’s
  • Pneumonia
  • Emphysema
  • Sex Drive
  • … and LOTS more
slide35

This is the damage

Seven Deadly Things

  • Junk - Inside Cells
  • Junk - Outside Cells
  • Cells - Too Few
  • Cells - Too Many
  • Mutations - Chromosomes
  • Mutations - Mitochondria
  • Protein Crosslinks

No new type of damage identified since 1982!

slide36

Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation

slide37

Structure of this talk

  • Repair versus retardation
  • Longevity escape velocity: concept
  • Some evidence that LEV is realistic
  • Specifics: the seven types of damage
  • Intracellular junk/medical bioremediation
  • The Methuselah Foundation
slide38

Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation

slide39

Aggregates: major examples

- Proteins in neurodegeneration

- Oxysterols in atherosclerosis

slide40

Autophagy in Alzheimer’s Disease

Dystrophic Neurites

IEM

Calnexin

Cat D

slide41

Endothelial

Cells

Lipid-engorged

Lysosome

Foam

Cell

slide42

Bioremediation: the concept

  • - Microbes, like all life, need an ecological niche
  • - Some get it by brawn (growing very fast)
  • - Some by brain (living off material than others can't)
  • Any abundant, energy-rich organic material that is hard to degrade thus provides selective pressure to evolve the machinery to degrade it
  • - That selective pressure works. Even TNT, PCBs…
slide43

R1 day 20

R5 day 71

R4 day 71

R1 day 71

R1 day 36

R2 day 71

R5 day 20

R2 day 36

R5 day 36

R3 day 71

R3 day 36

R4 day 36

1

2

5

7

9

11

12

15

Example: DGGE Results from Perchlorate-Reducing, Membrane Biofilm Reactors

slide44

Xenocatabolism: the concept

Graveyards:

- are abundant in human remains…

- accumulate bones (which are not energy-rich)…

- do not accumulate oxysterols, tau etc...

- so, should harbour microbes that degrade them

- whose catabolic enzymes could be therapeutic

slide49

Steps to biomedical application

Isolate competent strains; select by starvation

Identify the enzymes (mutagenesis, chemistry, genomics)

Make lysosome-targeted transgenes, assay cell toxicity

Assay competence in vitro (more mutagenesis/selection)

Construct transgenic mice, assay toxicity in vivo

Assay competence in disease mouse models

Test in humans as for lysosomal storage diseases

slide50

Structure of this talk

  • Repair versus retardation
  • Longevity escape velocity: concept
  • Some evidence that LEV is realistic
  • Specifics: the seven types of damage
  • Intracellular junk/medical bioremediation
  • The Methuselah Foundation
slide51

Funds: current status

  • $4.5M in Mprize pot
  • Research pot being spent as fast as we fill it
  • “LysoSENS” being funded (~$100k/yr) by 2005-2006 donations to the MF
  • “MitoSENS” being funded (~$150k/yr) by Peter Thiel’s donation of $500k
  • Thiel’s challenge pledge ($3M) is 1:2; our next goal is to match it in full (i.e. raise $6M)
slide52

Eventual organisational structure

  • Medium-term goal: proof of concept in mice
  • Strategy: solve/combine subgoals (SENS)
  • Procedure:
  • implement subgoals: ~350 people
      • scientifically interesting and respected
      • best done extramurally by academics
  • combine in same mice: ~150 people
      • scientifically tedious and unrewarded
      • best done in-house by paid technicians
slide53

Ramping up….

Level 1: funding of up to $300k per year guaranteed for at least 3 years. (This is where we are now.) Selected SENS strands supported at entry level (1 project/strand, 1-2 FTEs/project)

Level 2: funding of $300k-$3m per year, three years. (This is where we will be when the Thiel pledge is fully matched.) Six SENS strands supported at minimal level (1-3 projects/strand, 1-3 FTE/project)

slide54

Ramping up….

Level 3: funding of $3M-$20M per year guaranteed for at least five years. Grant applications solicited; 30-100 FTEs funded, across up to 30 projects

Level 4: funding of $20M-$100M per year, ten years. Physical facility (“Institute for Biomedical Gerontology”) set up (50-150 FTEs); extramural research support as in Level 3 (100-350 FTEs)

slide57

Why I am doing this

I offer no apology for using media interest in life extension to make the biology of ageing an exception to Planck’s observation that science advances funeral by funeral: lives, lots of them, are at stake.

de Grey 2005, EMBO Reports 6(11):1000

slide58

Shameless plug

Out now: $17.79 at Amazon